WO2013125987A1

WO2013125987A1 - Method for determining glucose concentration in human blood

Info

Publication number: WO2013125987A1
Application number: PCT/RU2013/000144
Authority: WO
Inventors: Евгений Львович СОКОЛОВ; Андрей Анатольевич ЧЕЧИК; Владимир Юрьевич ЕЛОХОВСКИЙ
Original assignee: Общество с ограниченной ответственностью "Алгоритм"; Общество С Ограниченной Ответственностью "Хилби"
Priority date: 2012-02-24
Filing date: 2013-02-22
Publication date: 2013-08-29
Also published as: US20150073242A1; MY164409A; KR20140126402A; RU2012106461A; CN104302229A; CN104302229B; EP2818108A4; JP2015512672A; US10667728B2; EP2818108B1; ES2637417T3; KR101687465B1; US20180035930A1; EP2818108A1; HK1204537A1; JP6063487B2; RU2518134C2

Abstract

The method involves measuring the impedance of a human body region at a high frequency (Z _HF) and a low frequency (Z _LF) with the aid of electrodes fastened to the human body. The value Z _HF is used to obtain the value of the volume of fluid contained in the tissues of the human body region. The value Z _LF is used to obtain the value of the volume of extracellular fluid contained in the tissues of the human body region. The amount of increase in the metabolic component in the volume of extracellular fluid which is related to the synthesis and utilization of energy carriers in the human body is determined by determining the increase in the value of the volume of all of the fluid in comparison with the previous measurement, determining the increase in the value of the volume of extracellular fluid in comparison with the previous measurement and subsequently calculating the difference between the aforesaid increases in the value of the volume of all of the fluid and the value of the volume of extracellular fluid. The amount of increase in the glucose concentration is determined by normalizing the above-mentioned amount of increase in the metabolic component in the volume of extracellular fluid. The glucose concentration in human blood G(t _k ) is determined by adding the above-mentioned amount of increase in the glucose concentration and the value of the glucose concentration in the blood determined at the previous measuring stage. The method enables a highly accurate, non-invasive determination of the glucose concentration in human blood.

Description

METHOD FOR DETERMINING CONCENTRATION

GLUCOSE IN HUMAN BLOOD TECHNICAL FIELD

The invention relates to methods for medical examination of a person by non-surgical methods, namely, to determining the concentration of glucose in human blood based on measuring the electrical resistance of a part of the body.

BACKGROUND OF THE INVENTION

Non-invasive methods for measuring glucose concentration in human blood are known, based on measuring the total electrical resistance (impedance) of a part of the human body or impedance components.

For example, a known method for indicating blood sugar [patent RU 2073242, G01N33 / 4, 1997], in which the patient’s blood sugar level is judged by the change in dielectric constant of a finger placed in the electric field of the transducer.

There is also known a method of controlling the amount of sugar in human blood [patent RU 2088927, G01N33 / 49, 1997], in which the measurement is carried out by changing the reactance of the oscillatory circuits included in the secondary circuits of the high-frequency generator, by direct human exposure to the elements of the oscillatory circuits. The amount of sugar in the blood is determined by the change in current in the secondary circuits of the high-frequency generator.

A known method [patent US 5792668, G01N27 / 00, 1998], in which the spectral analysis of reflected from the human body or passing through it high-frequency radiation. The measured parameter is the phase shift between the incident and reflected or transmitted waves, which characterizes the reactive component of the resistance of the body. The measured parameters of the phase spectrum judge the concentration of substances in the blood, in particular the concentration of glucose.

A known method is implemented by the device described in the certificate for utility model RU 9703, A61B5 / 00, 1999. In this device, the measurement of glucose concentration in the blood is based on measuring the impedance of a portion of the human body at two frequencies, determining the capacitive component resistance of the human body and the conversion of the obtained value of the capacitive component to the value of the concentration of glucose in the blood of the patient.

A known method of measuring the concentration of glucose in the blood non-invasive method [patent US 6517482, A61B5 / 00, 2003]. The method is based on measuring the resistance between two electrodes at a variety of frequencies and then determining the glucose concentration based on the measured values.

A known method for determining the concentration of glucose in the blood by a non-invasive method by measuring the electrical transfer functions using two pairs of four-electrode sensors [patent RU 2342071, А61В5 / 053, 2008]. The concentration of glucose in the blood is determined by a predefined mathematical model.

There is also a method for determining the concentration of glucose in the blood [patent US 7050847, A61B5 / 00, 2006], in which the impedance of a portion of a person’s body is measured using sensors at different frequencies. At high frequencies, the impedance value is associated with the volume of fluid in the body tissues, and at low frequencies, with the volume of extracellular fluid. The measured values determine the parameters of biological fluids in the body, which are used to judge the concentration of glucose in the blood.

However, the considered methods have a common drawback: the resulting estimate of the concentration of glucose in human blood is significantly inferior to the accuracy of measurements performed by direct - invasive methods. At the same time, invasive methods requiring a blood sample are clearly inferior to non-invasive methods in terms of convenience and safety.

The technical problem to which the present invention is directed is the creation of a non-invasive method for continuously determining the concentration of glucose in human blood, which has higher accuracy in comparison with known non-invasive methods.

SUMMARY OF THE INVENTION

The inventive method for determining the concentration of glucose in human blood, characterized in that sequentially at predetermined time intervals: measure the impedance of a portion of the human body at a high frequency and low frequency using electrodes attached to the human body and spaced relative to each other, based on the measured value of the impedance at high frequency, an estimate is obtained of the volume of liquid contained in the tissues of the portion of the human body between the electrodes,

based on the measured value of the impedance at a low frequency, an estimate of the volume of extracellular fluid contained in the tissues of a portion of the human body between the electrodes is obtained,

then the magnitude of the increment of the metabolic component of the said volume of extracellular fluid associated with the synthesis and utilization of energy in the human body is determined by determining the increment of the said estimate of the volume of fluid contained in the tissues of the human body between the electrodes, compared with the previous measurement, determining the increment of the said estimate of the extracellular volume the fluid contained in the tissues of the portion of the human body between the electrodes, compared with the previous measurement and subsequent calculation tracking the difference between said increment of estimating the volume of fluid contained in tissues of a portion of the human body between the electrodes and said increment of estimating the volume of extracellular fluid contained in tissues of a portion of the human body between electrodes,

determine the magnitude of the increment in the concentration of glucose in the blood of a person by normalizing said magnitude of said increment of the metabolic component of the volume of extracellular fluid,

and the glucose concentration in human blood is determined by summing the aforementioned increment of glucose concentration with the blood glucose concentration determined in the previous measurement step, wherein the glucose concentration in the first time interval is determined by summing the aforementioned glucose concentration in human blood obtained in the first interval time, with the initial value of glucose concentration.

The physical basis of the method is to measure the volume of fluid in a portion of a person’s body. Water in the human body makes up to 70% of its weight. Moreover, it does not form a single space, but is distributed in the tissues of the body. The boundaries of the liquid interface are the walls of blood vessels and cell membranes of which all body tissues are composed. It is customary to distinguish between three water spaces: intracellular fluid, intravascular fluid (blood plasma fluid) and intercellular fluid (fluid that fills the intercellular space. An intracellular fluid or fluid enclosed within tissue cells and red blood cells makes up about 30-40% of a person’s body weight.

Intravascular and intercellular fluids form the space of extracellular fluid, which makes up about 20% of the body weight of a person.

In each of these fluids, there are substances designed to support the life of cells or products of their vital functions, which are subject to removal or processing within the body. These substances during the life of the body move through the cell membrane from one space to another. One of the driving forces of this transfer is osmotic pressure, which depends on the difference in the concentration of substances on opposite sides of the membrane.

At rest, there is a dynamic balance of metabolic processes in the body. The appearance of a concentration gradient of osmotic pressure, for example, with the intake of glucose from the gastrointestinal tract after eating, causes water to move through the cell membrane in the direction of space with a higher concentration of substances dissolved in it. At the same time, the volumes of water sectors are changing. But then regulatory mechanisms are turned on, which seek to restore the disturbed balance between these spaces. That is, a change in the volume of water bodies of an organism has characteristic (cyclic) features. These features can be used as an indicator of the nature of metabolic processes in the body, for example, an increase in the concentration of glucose in the blood after a meal.

The basis of the method is to formulate an estimate of the increase or decrease in the concentration of glucose in the blood according to the dynamics of the volumes of its water spaces, which is evaluated during periodic measurements of the impedance values of a portion of the human body.

In special cases, the implementation of the method perform the following operations. At the beginning of the measurements, the initial value of the concentration of glucose in the blood is determined, which is produced by another - alternative method, non-invasive or invasive. This absolute value is individual for each person and determines not only the nature of the dynamics of changes in glucose concentration, but also its absolute values in different periods of human activity.

In particular, at least two electrodes mounted on some distance from each other, and it is preferable to install the electrodes in the peripheral parts of the body, for example, on the hand or finger.

Measurements of the impedance of a portion of the human body at high and low frequencies are performed with an interval of time from 1 second to 10 minutes, while for the convenience of the hardware implementation of the method, the time intervals are chosen the same.

Additionally, during measurements, the moment of food intake is recorded, and this fact is used to correct indicators of the dynamics of glucose intake into the human body.

In particular, when implementing the present method, based on the impedance values of a portion of a human body measured at high and low frequencies periodically at time t _k , the following parameters are determined:

1) the volume of fluid contained in the tissues of a portion of the human body between the electrodes W _sum (t _k ) is determined by the formula:

W _sum {tk) = - L ² / z _HF (t _k ),

where: L is the distance between the electrodes;

Z _HF {t _k ) is the value of the impedance of a portion of the human body, measured at a high frequency HF at time t _k ;

- calibration factor determined by the formula:

where: V _sum is the previously obtained value of the volume of fluid contained in the tissues of a portion of the human body between the electrodes;

Z _HF - pre-obtained value of the impedance of the human body at a high frequency HF;

2) the volume of extracellular fluid contained in the tissues of a portion of the human body between the electrodes W _out (i _k ) is determined by the formula:

W _{0 Ut} (t _k ) = B - L ² / z _LF {t _k ),

where: ^ _LF ^ fk) ~ the value of the impedance of a portion of the human body, measured at a low frequency LF at time t _k ;

In - calibration factor, determined by the formula:

B = V _{0 Ut} - Z _LF / L ² ; where: V _out is the previously obtained value of the volume of extracellular fluid contained in the area of the human body between the electrodes;

Z _LF - pre-obtained value of the impedance of the human body at a low frequency LF;

3) the value of the increment of the metabolic component of the volume of extracellular fluid & W _osm {t _k ) is determined by the formula:

where: ^ sum i -i) ~ the volume of fluid contained in the tissues of the portion of the human body between the electrodes for the previous measurement at time t _k _ _x ;

W _out ) is the volume of extracellular fluid contained in the tissues of a portion of the human body between the electrodes for the previous measurement at time

K _a is a coefficient depending on the value of the human hematocrit and which is selected in the range from 1.2 to 2.1;

4) the magnitude of the increment in the concentration of glucose in human blood AG (t _k ) is determined as:

AG {t _k ) = AW „ _m (t _k ). K _E - K _PR / K _g ,

where: K _g - normalization coefficient, which is selected in the range from

0.005 L ² mmol ^-1 to 0.006 L ² mmol ^~ \

To _E is a coefficient depending on food intake, and when determining the concentration of glucose in human blood before eating, the value of K _{E is} selected in the range from 0.23 to 0.4, and when determining the concentration of glucose in human blood after eating, the value of K _E selected in the range from 0.6 to 1.0;

K _PR is the coefficient used to determine the concentration of glucose in human blood in the period from 20 minutes to 45 minutes after a meal and takes the value "1" or "-1" depending on the sign of the magnitude of the mentioned increment of the metabolic component of the volume of extracellular fluid according to the following to the rule:

K _PR = l, if the mentioned increment of the metabolic component of the extracellular fluid volume W _osm (t _k ) is greater than 0, K _PR - - \ if the mentioned increment of the metabolic component of the extracellular fluid volume & W _0Sm (t _k ) is less than 0.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated by the following graphic materials.

In FIG. 1 shows the results of determining the concentration of glucose in the blood for the first volunteer.

In FIG. 2 shows the results of determining the concentration of glucose in the blood for the second volunteer,

In FIG. 3 shows the results of determining the concentration of glucose in the blood for the third volunteer.

Moreover, in FIG. 1a, FIG. 2a and FIG. For graphs of changes in glucose concentration, determined by various methods, including the method according to the invention, are shown, and FIG. lb, FIG. 2b and FIG. H3 plots the measured impedance and temperature.

BEST MODE FOR CARRYING OUT THE INVENTION

The method is as follows.

Two electrodes spaced apart from each other by a distance L are fixed on a part of the human body. The most effective installation of electrodes on the peripheral parts of the human body, for example, on the arm, in particular on the forearm or finger. The best result will be achieved if these are ring electrodes covering the forearm or finger.

Since the method in accordance with the present invention is based on calculating the increment values of glucose concentration in human blood, followed by summing these values, before starting the impedance measurements, the glucose concentration in the blood is measured in any other available way, invasive or non-invasive, which is taken as the initial value.

The measurement of the impedance of a portion of the human body between the electrodes is carried out at two frequencies: a high frequency HF and a low frequency LF. High frequency HF is selected in the range from 200 kHz to 2 MHz, low frequency LF is selected in the range from 20 kHz to 80 kHz. The measurement of the total electrical resistance or components of the total electrical resistance of a portion of human tissues can be carried out using one of the known methods, in particular, by using high-frequency oscillations and measuring the resistance with capacitive sensors. Measure the impedance of a portion of the human body at selected time intervals in the range from 1 s to 10 minutes.

During the measurements, the time of food intake, which characterizes the influx of glucose into the human body from the outside, is recorded in order to determine the increment of the metabolic component of the extracellular fluid volume associated with glucose, taking into account the time elapsed after the start of food intake recorded during the measurements.

Based on the initial value of the concentration of glucose in the blood, current sequential measurements of the impedance of a portion of the human body at high and low frequencies and taking into account the time of the next meal, the concentration of glucose in the blood of a person is determined as follows.

1. Based on the value of the impedance of a portion of the human body measured at a high frequency HF at a time point - Z _HF (t _k ), and taking into account the distance L between the electrodes, the volume of fluid contained in the tissues of the portion of the human body between the electrodes W _sum {t _k ) , as:

W _sum (t _k ) = A - L ² lz _HF (t _k ),

where: - calibration factor determined by the formula:

Here, V _sum is the previously obtained value of the volume of fluid contained in the tissues of a portion of the human body between the electrodes. This value can be obtained, for example, by calculation based on the anatomical relationships of the selected portion of the human body for measuring the impedance. Also, to determine the calibration coefficient A, the impedance value of the human body portion at a high frequency Z _{HF is used} , obtained previously before the measurements related to the determination of glucose concentration in human blood in accordance with the present invention.

2. Using the value of the impedance of a portion of the human body measured at a low frequency LF at a point in time - Z _LF {t _k ), and taking into account the distance L between the electrodes, the volume of extracellular fluid contained in the tissues of the portion of the human body between the electrodes W _out {t _k ), as:

W _{0 Ut} (t _k ) = B. L ² lz _LF {t _k ),

where: B - calibration factor determined by the formula: Here V _out is the previously obtained value of the volume of extracellular fluid contained in the portion of the human body between the electrodes. This value can be obtained, for example, by calculation based on the anatomical relationships of the selected portion of the human body for measuring the impedance. Also, to determine the calibration coefficient B, the impedance value of the human body portion at a low frequency Z _{LF is used} , obtained previously before the measurements related to the determination of glucose concentration in human blood in accordance with the present invention.

3. Next, the obtained values of the volume of fluid contained in the tissues of the portion of the human body between the electrodes and the volume of extracellular fluid contained in the tissues of the portion of the human body between the electrodes are used to calculate the increment of the metabolic component of the volume of extracellular fluid & W _osm {t _k ). In ^{this case} , the values of liquid volumes obtained for measuring the impedance at a time and for the previous measurement at a time t _k _ _{l are used} . The value of the increment of the metabolic component of the volume of extracellular fluid is determined by the formula:

where: Wsumi) ~ the volume of fluid contained in the tissues of a portion of the human body between the electrodes for the current measurement at a point in time;

^ sum ^ ki) ^~ ° the volume of fluid contained in the tissues of a portion of the human body between the electrodes for the previous measurement at time t _k _ \; fV _out (t _k ) is the volume of extracellular fluid contained in the tissues of a portion of the human body between the electrodes for the current measurement at time t _k ;

W _out {t _k _ _x ) is the volume of extracellular fluid contained in the tissues of a portion of the human body between the electrodes for the previous measurement at time

To _a - coefficient depending on the value of the human hematocrit and which is selected in the range from 1.2 to 2.1. 4. Based on the obtained value of W _osm (t _k ) and taking into account the moment of food intake, the magnitude of the increment in the concentration of glucose in human blood is determined:

AG (t _k ) = AW _osm (t _k ) - K _E. K _PR / K _g , where: K _g is the normalization coefficient, which is chosen in the range from 0.005 L ² mmol ^-1 to 0.006 L ² mmol ^"1 .

K _PR = l, if the mentioned increment of the metabolic component of the extracellular fluid volume AW _osm (tf ^) is greater than 0,

K _PR = - \ if the mentioned increment of the metabolic component of the extracellular fluid volume AW _osm t _k ) is less than 0.

5. The final value of the concentration of glucose in human blood at time is determined as follows:

k = 1

where: G _Q - the initial value of the concentration of glucose in human blood;

G (t _j ) - the values of all increments in the concentration of glucose in the blood of a person obtained from the beginning of the measurement to the point in time, and = {1}.

Thus, knowing the initial value of the concentration of glucose in human blood G ₀ and periodically measuring the impedance of a portion of the human body at high and low frequencies - Z _HF (t _k ) and Z _LF (t _k ), it is possible to determine the current value of glucose concentration in human blood . The present invention can be implemented in the form of a fairly simple measuring device with the ability to calculate these parameters characterizing the change in the volume of water spaces in human tissues, and as a result, the current value of glucose concentration in human blood, including taking into account its individual physiological characteristics and moments of food intake.

EXAMPLES

Example 1. Processing the measurement results of a healthy Volunteer 1.

A 38-year-old man, healthy, took a nutritional load of 300 g of a sweet drink (Pepsi Cola). In FIG. lb shows graphs of changes in the values of the impedance Z _HF and Z _LF and temperature T ° C, taken from the sensor located on the forearm, and in FIG. 1a shows a graph of the change in glucose concentration in the blood of Volunteer 1. Dots indicate the values of blood samples taken during the measurements (Roche Accu-Chek Active glucometer was used). The average error in the measurement interval of 150 minutes was 6.8%.

Example 2. Processing the measurement results of a healthy Volunteer 2.

A 45-year-old man, healthy, took the food load in the form of two glasses of 200 g of a sweet drink (Pepsi Cola). In FIG. 2b shows graphs of changes in the values of the impedance Z _HF and Z _LF and temperature T ° C, taken from the sensor located on the forearm, and in FIG. 2a is a graph of changes in the glucose concentration in the blood of Volunteer 2. Dots indicate the values of blood samples taken during the measurement (Roche Accu-Chek Active glucometer was used). The average error in the measurement interval of 140 minutes was 7.2%.

Example 3. Processing the measurement results of a healthy Volunteer 3.

A 42-year-old man, healthy, took a combined food load in the form of one banana and 200 g of a sweet drink (Pepsi Cola). In FIG. H shows the changes in the values of the impedance Z _HF and Z _LF and temperature T ° C, taken from the sensor located on the forearm, and in FIG. For - a graph of changes in the concentration of glucose in the blood of Volunteer 3. Dots indicate the values of blood samples taken during the measurement (used Roche Accu-Chek Active glucometer). The average error in the measurement interval of 150 minutes was 9.5%.

The tests showed that the inventive method can provide a smaller error in determining the concentration of glucose in human blood in comparison with known non-invasive methods.

Claims

CLAIM

1. A method for determining the concentration of glucose in human blood, characterized in that sequentially, at predetermined time intervals, the impedance values of a portion of the human body are measured at a high frequency and a low frequency using electrodes fixed to the human body and spaced apart from each other,

based on the measured value of the impedance at high frequency, an estimate is obtained of the volume of liquid contained in the tissues of the portion of the human body between the electrodes,

and the glucose concentration in human blood is determined by summing the aforementioned increment of glucose concentration with the value of the glucose concentration in the blood determined in the previous measurement step, wherein the glucose concentration in the first time interval is determined by summing the aforementioned glucose concentration in human blood obtained in the first interval time, with the initial value of glucose concentration.

2. The method according to p. 1, characterized in that the initial value of the concentration of glucose in the blood is determined by an alternative method, for example, invasive.

3. The method according to p. 1, characterized in that the measurement of the impedance of a portion of the human body is carried out using at least two electrodes.

4. The method according to p. 3, characterized in that the electrodes are installed on the peripheral parts of the body, for example, on the arm or finger.

5. The method according to p. 1, characterized in that the measurement of the impedance of the human body area is carried out with an interval of time from 1 second to 10 minutes.

6. The method according to p. 1, characterized in that the said volume of fluid contained in the tissues of a portion of the human body between the electrodes W _sum (t _k ) is determined by the formula:

where: L is the distance between the electrodes;

Z _HF (t _k ) is the value of the impedance of a portion of the human body, measured at a high frequency HF at time t _k ;

- calibration factor determined by the formula:

said volume of extracellular fluid contained in the tissues of a portion of the human body between the electrodes W _out (t _k ) is determined by the formula: W _0Ut (t _k ) = B - L ² lz _LF {t _k ),

where: Z _LF (t _k ) is the value of the impedance of a portion of the human body, measured at a low frequency LF at time t _k ;

- calibration factor determined by the formula:

where: V _OUT is the previously obtained value of the volume of extracellular fluid contained in the portion of the human body between the electrodes; Z _LF - pre-obtained value of the impedance of the human body at a low frequency LF;

the mentioned value of the increment of the metabolic component of the volume of extracellular fluid AW _osm (t _k ) is determined by the formula:

Δ W _osm (t _k ) = [W _sum (/ .. - W _sum (t _k )] - K _a [W _out (** _,) - W _out (t _k )],

where: W _sum {t _k _ \) is the volume of fluid contained in the tissues of the portion of the human body between the electrodes for the previous measurement at time t _k _ _x ;

W _out t _k _) is the volume of extracellular fluid contained in the tissues of a portion of the human body between the electrodes for the previous measurement at time t _k _ _x ;

To _a - coefficient depending on the value of the human hematocrit and which is selected in the range from 1.2 to 2.1;

and the magnitude of the increment in the concentration of glucose in human blood AG (t _k ) is defined as

AG (t _k ) = AW _osm (t _k ) - K _E - K _PR / K _g , where: Kg is the normalization coefficient, which is chosen in the range from

0.005 L ² mmol ^-1 to 0.006 L ² mmol ^"1 .

K _PR = 1, if the mentioned increment of the metabolic component of the extracellular fluid volume W _osm (t _k ) is greater than 0,

K _PR = - \ if the mentioned increment of the metabolic component of the extracellular fluid volume AfV _osm (t _k ) is less than 0.